Dosage forms in which easy swallowing by patients is taken into consideration are scarce in spite of the existence of various known dosage forms of pharmaceutical preparations for oral administration use. Accordingly, great concern has been directed toward the development of a dosage form which can easily be handled, especially, by the aged or children having difficulty in swallowing oral preparations.
For example, in the case of tablets and capsules frequently used as oral preparations, many patients of the aged or children having weak swallowing power are unwilling to take these solid preparations complaining that the drug is difficult to swallow or stops in the pharynx or gullet. Chewable tablets are not suitable for the aged or children having weak chewing power.
In the case of powders and granules, they are difficult to swallow because of their aptness to remain in the buccal cavity and, therefore, to cause an unpleasant feeling in the mouth. In some cases, the aged will be choked with powders or feel a pain or unpleasantness due to granules gotten in between false teeth. In addition, powders and granules have to be used after tearing each package, but the aged or children often have difficulty in tearing the package or spill a portion of its contents.
To take these oral preparations, it is necessary to use water, and the aged or children especially require a large volume of water in many cases because of the swallowing difficulty. However, there is a situation that it is necessary to drink water moderately, especially, before retire to bed because of the urination problem at night. In addition, in the case of patients who have to take oral preparations constantly while making daily life, water can hardly be obtained in certain cases depending on circumstances, thus sometimes entailing decline in the compliance.
Syrups and the like are regarded as desirable dosage forms for the aged or children, but the aged or children who have difficulty in measuring the necessary volume cannot be expected to use such preparations in correct dose. In addition, since there are many aged patients who can hardly take liquid preparations to mouths by themselves, such dosage forms cannot always be regarded as suitable dosage forms for the aged and children in view of the trouble during drug-taking, except for a case in which a patient can ask a nurse for a helping hand.
Taking such circumstances into consideration, attempts have been made to develop the following intrabuccally dissolving preparations as the preparation suitable for the aged and children. However, they are not practically sufficient because of the disadvantages such as (1) complex production steps and new plant and equipment investment required for the production of such preparations, (2) limitation in the application of the active ingredients and (3) difficulty in handling the preparations due to their inadequate hardness accompanied by the quick disintegration and dissolution in the buccal cavity pursued as characteristics of the preparations.
When the forthcoming social condition of advanced age is taken into consideration, development of the practical preparation which can be used easily, especially, by the aged seems to be an immediate need, because the morbidity rate of chronic diseases increases with advance in age and patients of advanced age have a tendency to take drugs for a long period of time. Also, in order to keep the quality of life, it is desirable to develop the preparation which can be easily swallowed and handled in accordance with the ability and life condition of each patient.
JP-B-58-24410 corresponding to U.S. Pat. No. 4,134,943 (the term "JP-B" as used herein means an "examined Japanese patent publication") discloses a process for the production of porous tablets having an excellent disintegration property, which comprises mixing contents of the tablet with a solvent that is inert to the contents of the tablet and that freezes at a temperature in the range of from -30.degree. C. to +25.degree. C., said solvent being used in an amount of from 5 to 80% by weight based on the total mixture, solidifying the mixture by putting the mixture in an inert cooling medium, compressing the solidified mixture at a temperature lower than the freezing point of the solvent to make the mixture into tablets, and then conducting volatilization of the solvent by means of freeze drying, spontaneous drying or the like.
JP-A-3-86837 corresponding to U.S. Pat. Nos. 5,039,540 and 5,079,018 (the term "JP-A" as used herein means an "unexamined published Japanese patent application") discloses an easily dissolvable carrier material having a sufficient strength which is obtained by allowing a composition comprising a water-soluble hydrous gel or a foam substance to contact with an anhydrous organic liquid desiccating agent such as anhydrous ethanol at a temperature of about 0.degree. C. or lower until all of the water content is substantially removed from the composition.
Each of these production processes, however, requires complex production steps and additional manufacturing facilities such as a freeze dryer and the like, thus entailing high production cost.
JP-A-2-32014 corresponding to EP-B-345628 discloses a solid preparation in the form of molded tablets which are suitable for oral administration. However, since these tablets are obtained by preparing a wet mass using ethanol/water or water alone and drying the mass in a mold, the process to produce these tablets has poor productivity in comparison with the common production processes.
JP-A-61-15830 corresponding to EP-A-166440 discloses an antacid composition having a porous ultra-fine crystal structure, which contains an antacid agent, a sweet material for confectionery use and confectionery base containing a plasticizer. JP-A-3-209336 discloses a pharmaceutical composition which is obtained by uniformly dispersing particles of at least one pharmaceutically active compound in the crystal matrices of a crystalline sugar alcohol derived from at least one monosaccharide or polysaccharide. Each of these production processes, however, has a disadvantage in that the application of active ingredients is limited in view of the heat-stability because of the step to melt sugar components at 100.degree. C. or higher.
In addition, though an intrabuccally dissolving pharmaceutical preparation is now commercially available from R. P Scherer under a trade name of "Zydis", it is highly costly because it requires an additional manufacturing facility such as a freeze dryer or the like due to its production by freeze drying and it requires a prolonged period of time for the production. Also, since the pharmaceutical preparation obtained by freeze drying has a week strength, it requires special cautions for its handling and, therefore, is not satisfactory for the use by the aged. For example, unlike the case of usual tablets, this preparation cannot easily be taken out by pressing the package when contained in the blister package (PTP: press through package).
The above-mentioned intrabuccally dissolving pharmaceutical preparation obtained by freeze drying (to be referred to as the "freeze-dried preparation" hereinafter) is excellent especially in disintegration and dissolution, but is not satisfactory in terms of its storage life because it does not have a sufficient hardness for keeping its dosage forms during the production steps and distribution stages.
In addition to the conventional freeze drying method, other intrabuccally dissolving pharmaceutical preparations produced by tabletting have been reported.
JP-A-5-271054 corresponding to EP-A-553777 discloses that intrabuccally dissolving tablets having an adequate strength and a porous structure which quickly disintegrate and dissolve in the buccal cavity can be obtained by preparing a mixture of an active ingredient, a saccharide and water in a sufficient amount to wet the surface of the saccharide granules, tabletting the mixture into tablets and drying the tablets.
Each of the above-mentioned intrabuccally dissolving pharmaceutical preparations obtained by tabletting (to be referred to as the "tabletted preparation" hereinafter) does not require the production steps for obtaining freeze-dried preparations and is satisfactory in terms of the storage life due to its sufficient hardness for keeping its dosage forms during the distribution stages. However, since the tabletted preparation is produced by simply subjecting a mixture or a blend to tabletting, there is still great room for the improvement of its quick disintegration and dissolution in the buccal cavity which are the characteristics of intrabuccally dissolving pharmaceutical preparations.
In addition, the following documents focused on the moldability of the saccharide and on the direct tabletting. JP-A-5-310558 discloses that, when mannitol or lactose having low binding property and poor moldability is blended with sorbitol granules having a bulk density of less than 60 g/100 ml, amounts of other additives having high moldability such as cellulose compounds, acrylic acid compounds, gelatin and the like can be reduced and solid pharmaceutical compositions having excellent disintegration property can be obtained. Similarly, JP-A-59-118058 corresponding to U.S. Pat. Nos. 4,507,511 and 4,605,794 and DE-A-1617638 disclose a preparation in which sorbitol having a particular bulk density is used. These documents may suggest that sorbitol having a particular bulk density can work as a binding agent when the direct tabletting is carried out. However, the inventions of these documents relate to an additive and a production process for obtaining tablets having an improved hardness under the usual tabletting pressure for making tablets, and their object is a production of an additive for the direct tabletting.
According to JP-A-5-170669 corresponding to EP-A-509606, moldability of lactose is improved by adding a sugar alcohol to a lactose having a high p-lactose content and drying the aqueous solution thereof by means of roller drying. However, since special saccharides are required, these processes are complex and expensive and, therefore, are not practical.
U.S. Pat. No. 4,698,101 discloses a pharmaceutical adjuvant based on fructose which is obtained by granulating fructose with an aqueous maltose solution and which can be subjected to direct tabletting.
JP-A-4-505918 based on a PCT application discloses a pharmaceutical adjuvant based on fructose which is obtained by granulating fructose with an aqueous polyol solution containing sorbitol, maltitol, lactitol, xylitol, mannitol, isomaltol, or a mixture thereof and which can be subjected to direct compression.
Although fructose is used as a core for the granulation, these documents relate to the conventional tablets, not to an intrabuccally dissolving tablets. In addition, there is a problem that, when handled usually, the granules absorb moisture due to the high hygroscopicity of fructose and, as a result, a sufficient fluidity cannot be obtained, resulting in a tendency to cause hindrance to the takeletting.